Eosinophilic esophagitis (EE) is an emerging worldwide food allergic disorder associated with polysensitization to multiple food allergens, resulting in greatly restricted diets and chronic gastroesophageal reflux disease (GERD)-like symptoms. There is a paucity of molecular and genetic insight into EE, a poor understanding of the relationship between IgE-triggered food allergy and EE, and there is currently no approved drug for this food allergic disease, highlighting the need for innovative fundamental studies focused on EE. We have shown that EE appears to have a strong genetic component based on the frequent presence of a familial inheritance pattern and the high sibling risk ratio (~80-fold). Based on screening a custom DNA array containing 738 SNPs, we have identified an association of EE with SNPs associated with the gene encoding thymic stromal lymphopoietin (TSLP), a key cytokine known to regulate Th2 cell polarization. Notably, using an independent genome wide association study (GWAS) approach, we have preliminarily linked EE with the same promising genetic locus (chromosome 5q22 near the TSLP and WDR36 genes). The fact that two independent approaches have linked EE with the same genetic region, and the finding that this region contains the gene for a key protein involved in Th2-associated immunemediated responses, highlights our interest in focusing on this finding. Our central hypothesis is that EE has strong genetic components that can be elucidated by a candidate gene approach focused on genes involved in asthma and allergy and by a GWAS analysis. Using these approaches, our preliminary studies have led us to the hypothesis that EE susceptibility involves the TSLP/WDR36 locus, a region known to be involved in allergic responses. We are well positioned to answer key genetic questions concerning EE based on a multi-faceted approach: (1) genetic analysis of EE DNA samples using relatively large and unique cohorts of well-characterized EE patient samples obtained from multiple CoFAR sites; (2) our ability to validate lead genetic candidates using a cohort of parent offspring trios; and (3) our ability to test genotype/phenotype relationships using our EE sample databank. We will pursue candidate gene validation (Aim 1), genome wide association study analysis (Aim 2) and biological assessment of one lead candidate TSLP (Aim 3).